The purpose of these studies is to better understand energy metabolism in tissues in vivo. To this end, this laboratory specializes in the use of non-invasive and non-destructive optical and NMR techniques to evaluate the physiological function of the heart. Of special interest is the control of oxidative phosphorylation and blood flow in the intact heart. The following major findings were made over the last year: 1) We established that the ATP-sensitive K channel contributes to the maintenance of coronary vascular tone under normal in vivo conditions. Studies with inhibitors and vaso-dilators have demonstrated that the ATP- sensitive K channel regulates the coronary vascular tone by modulating the smooth muscle membrane potential. 2) Studies on the effects of afterload and pacing work on the isolated heart revealed that the mitochondrial NADH redox state is constant despite 2- to 3-fold increases in flux through this key intermediate. This indicates that NADH cannot be the primary regu-lator of oxidative phosphorylation in the intact heart and that the NADH redox state is highly buffered by substrate oxidation in intact tissues in contrast to isolated mitochondria. 3) 13C, 31P NMR and optical spectroscopy studies on the utilization of lactate and pyruvate in the intact rabbit heart and in vivo dog heart revealed several new metabolic regulatory processes. Pyruvate was found to be a "preferred" substrate, which is also capable of increasing the phosphorylation potential (i.e. energy available to do work) of the heart, even in vivo. Lactate actively metabolized did but not in-crease the phosphorylation potential. Lactate specifically inhibited glycolysis perhaps via the generation of a cytosolic sugar phosphate compound. We believe the differences in lactate and pyruvate metabolism on cardiac energetics involve the cytosolic NADH redox state.